1. Field of the Invention
Mycophenolic acid glucoside is useful in the treatment of psoriasis and gout; it also inhibits the growth of transplanted tumor cells in mice and rats (see R. E. Holmes, U.S. Pat. No. 3,903,071).
Mycophenolic acid and mycophenolic acid glucoside have structures 1 and 2, respectively: ##STR1## 1 R=H (mycophenolic acid); 2 R=.beta.-D-glucopyranosyl (mycophenolic acid glucoside).
A chemical name for mycophenolic acid glucoside is 6-[4-(.beta.-D-glucopyranosyl)-6-methoxy-7-methyl-3-oxo-5-phthalanyl]-4-me thyl-4-hexenoic acid.
The method of preparing mycophenolic acid glucoside which is described in U.S. Pat. No. 3,903,071 is a complex chemical one. This method requires many steps and is not very practical on a manufacturing scale.
2. The Prior Art
A group at Imperial Chemical Industries Ltd. (ICI) conducted an extensive screening program for microorganisms that could modify mycophenolic acid. Through their studies, the ICI group found over 20 microbial transformation products of mycophenolic acid. Mycophenolic acid glucoside, however, was not among the products that were found. [See D. F. Jones, et al., J. Chem. Soc. (C) 1970, 1725-1737].
There have been examples of microbiological glucosylation of organic compounds. Vanek and his group at the Czechoslovak Academy of Sciences have accomplished glucosylation of dihydroxyanthraquinones. Specific compounds that were glucosylated were alizarin, quinizarin, chrysazin, and anthraflavin. [See Z. Vanek et al., Folia Microbiol. 18, 524-526 (1973); N. Hovorkova, et al., Coll. Czech. Chem. Commun. 39, 662-667 (1974); and J. Mateju, et al., Folia Microbiol. 19, 307-316 (1974)].
Yamada, et al., at the University of Kyoto reported on the glucosylation of pyridoxine. They found that this reaction is catalyzed by various .alpha.-glucosidases. The enzymes Takadiastase B (Aspergillus), mold maltase (A. niger), and yeast .alpha.-glucosidase all catalyzed the glucosylation reaction. [See F. Kawai, et al., Agr. Biol. Chem. 35 (2), 184-190 (1971); ibid. 35 (11), 1660-1667 (1971); and ibid. 37 (8), 163-165 (1973)].
More recently, Kieslich, et al., reported that an enzyme produced by Sporotricum sulfuresens catalyzed the glucosylation of 5,7-dichloro-2-methyl-8-quinolinol to give the 4-O-methyl-.beta.-glucoside derivative. A 4-O-methyl-.beta.-glucoside derivative of 6-hydroxytetralone was similarly formed. [See K. Kieslich, et al., Chem. Ber. 109, 2259-2265 (1976)].
Brannon et al. reported the preparation of a glucosyl derivative of the polyether antibiotic monensin (metabolite A-27106) using the enzyme system of Streptomyces candidus NRRL 5449 in U.S. Pat. No. 3,932,619.
Notwithstanding the glucosylation reactions known in the art, it is impossible to predict whether glucosylation will occur when a chemically different substrate is presented. Enzymatic glucosylation of a structure such as that of mycophenolic acid has not been reported. The fact that mycophenolic acid can be successfully glucosylated enzymatically was especially surprising since the extensive microbial transformation studies of the ICI group did not give such a product.